Ikuko Yano

Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients.

Objective The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype. Methods Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program. Results CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5*1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17–1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5*3/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan–Meier method, was significantly associated with the recipients but not donors CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81). Conclusion These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.

Detection of 22 antiepileptic drugs by ultra-performance liquid chromatography coupled with tandem mass spectrometry applicable to routine therapeutic drug monitoring.

The purpose of this study was to develop an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method of 22 antiepileptics for routine therapeutic monitoring. The antiepileptics used in the analyses were carbamazepine, carbamazepine-10,11-epoxide, clobazam, N-desmethylclobazam, clonazepam, diazepam, N-desmethyldiazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, N-desmethylmesuximide, nitrazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide. After protein precipitation of 50u2009μL plasma with methanol, the supernatant was diluted with water or was evaporated to dryness and reconstituted with mobile phase in the case of benzodiazepines. Separation was achieved on an Acquity UPLC BEH C₁₈ column with a gradient mobile phase of 10u2009mm ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.4u2009mL/min. An Acquity TQD instrument in multiple reaction monitoring mode with ion mode switching was used for detection. All antiepileptics were detected and quantified within 10u2009min, with no endogenous interference. All the calibration curves showed good linearity in the therapeutic range (r² u2009<u20090.99). The precision and accuracy values for intra- and inter-assays were within ±15% except for phenobarbital and tiagabine. A good correlation was observed between the concentration of clinical samples measured by the new method described here and the conventional methods. The values of carbamazepine and phenytoin by UPLC-MS/MS were lower than those detected by the immunoassays, which might be caused by the cross-reaction of antibodies with their metabolites. In conclusion, we developed a simple and selective UPLC-MS/MS method suitable for routine therapeutic monitoring of antiepileptics.

Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients.

Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(+ or -) heterozygous mice were comparable with those in Mate1(+ or +) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant. There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients.

Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

BackgroundWe investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel.MethodsPaclitaxel was administered at 175u2009mg/m2 or 150u2009mg/m2 to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated.ResultsTotal body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-µM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel.ConclusionThe hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.

Prospective Evaluation of the Bayesian Method for Individualizing Tacrolimus Dose Early After Living‐Donor Liver Transplantation

Tacrolimus is widely used to prevent acute rejection after transplantation, but achieving therapeutic blood concentrations of tacrolimus is often difficult because of large pharmacokinetic variability. In this study, the applicability of the Bayesian method to individualize tacrolimus dose was prospectively examined. Twenty adult recipients (Bayesian group) and another 20 adult patients (control group), all of whom underwent living‐donor liver transplantation, were enrolled in this study. In the Bayesian group, the dose of tacrolimus during the first 3 and 4 weeks after surgery was adjusted with the Bayesian method using a population pharmacokinetic model, targeting a trough level of 5 to 12 ng/mL. The interindividual variability in tacrolimus concentrations was significantly reduced in the Bayesian group compared with the control group (average percentage coefficient of variation for all occasions, 32% vs 44% and 31% vs 39% in the first 3 and 4 weeks, respectively). In addition, more patients achieved the target concentrations in the Bayesian group than in the control group (average for all occasions, 85% vs 59% and 83% vs 70% in the first 3 and 4 weeks, respectively). These findings suggest that the Bayesian method can be used to calculate maintenance doses of tacrolimus in adult patients early after living‐donor liver transplantation.

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

PurposeTacrolimus pharmacokinetics and calcineurin activity in peripheral blood mononuclear cells (PBMCs) were investigated in adult patients undergoing primary living-donor liver transplantation (LDLT) in order to clarify the significance of monitoring the tacrolimus blood trough concentration during the early post-transplantation period.MethodsFourteen patients were enrolled in this study, and time-course data following the oral administration of a conventional tacrolimus formulation twice daily were obtained at 1 and 3xa0weeks post-transplantation. The concentration of tacrolimus in whole blood and calcineurin activity in PBMCs were measured.ResultsThe apparent clearance of tacrolimus significantly increased at 3xa0weeks versus 1xa0week post-transplantation, although the trough concentration did not significantly differ at these time points. The concentration at each sampling time, except at 1xa0h post-dose, correlated well with the area under the concentration–time curve from 0 to 12xa0h (AUC0–12). Neither the concentration at the trough time point nor AUC0–12 was correlated with the area under the calcineurin activity–time curve from 0 to 12xa0h; however, calcineurin activity at the trough time point was strongly correlated with the latter (r2u2009>u20090.92).ConclusionsBased on these results, trough concentration monitoring can be considered an appropriate procedure for routine tacrolimus dosage adjustment in adult LDLT patients. Monitoring of calcineurin activity at the trough time point was also found to be potentially useful for predicting the immunological status of the patient during the tacrolimus dosing interval.

Degree of freezing does not affect efficacy of frozen gloves for prevention of docetaxel-induced nail toxicity in breast cancer patients

PurposeFrozen gloves (FG) are effective in preventing docetaxel-induced nail toxicity (DNT), but uncomfortable. The preventive effect of FG for DNT was compared using a standard (−25 to −30°C) or more comfortable (−10 to −20°C) preparation.MethodsBreast cancer patients receiving docetaxel were eligible. Each patient wore an FG (prepared at −10 to −20°C for 90xa0min) for 60xa0min without replacement on the right hand. The left hand was protected by standard methods (FG prepared at −25 to −30°C overnight and worn for 90xa0min with replacement at 45xa0min). The primary endpoint was DNT occurrence at 5xa0months. Secondary endpoints included docetaxel exposure [cumulative dose and area under the blood concentration time curve (AUC)] until DNT occurrence and discomfort from FG. The pharmacokinetics of docetaxel was assessed.ResultsFrom 23 patients enrolled between December 2006 and June 2010, seven who received docetaxel for less than 5xa0months were excluded from evaluation. The median accumulated docetaxel dose was 700xa0mg/m2 (340–1430xa0mg/m2). Within 5xa0months of FG use, none developed protocol-defined DNT in either hand. Two patients (13%) developed DNT at 7.2 and 7.3xa0months, respectively, both at −10 to −20°C. In the control hand (−25 to −30°C), discomfort occurred in 92% of the cycles, compared to 15% in the experimental hand (−10 to −20°C). Five patients (22%) experienced pain at −25 to −30°C, but none did at −10 to −20°C. The degree of docetaxel exposure was not related to DNT occurrence in our study.ConclusionA convenient preparation of FG at −10 to −20°C is almost as effective as a standard preparation at −25 to −30°C, with significantly less discomfort.

Effect of itraconazole on the pharmacokinetics of everolimus administered by different routes in rats.

The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2u2009mg/kg) or intraintestinally (0.5u2009mg/kg). Blood concentrations of everolimus were measured up to 240u2009min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20u2009mg/kg) significantly increased the area under the concentration–time curve (AUC) of intraintestinally administered everolimus about 4.5‐fold, but even at 50u2009mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50u2009mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2‐fold. Using a value for hepatic blood flow from the literature (50u2009ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20u2009mg/kg) changed the apparent intestinal extraction by 0.26‐fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50u2009mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first‐pass extraction of this drug. Copyright